Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group.

The heterogeneity of early stage CLL challenges prognostication, and refinement of prognostic indices for risk-adapted management in this population is essential. The aim of the multicenter, prospective CLL1 trial was to explore a novel prognostic model (CLL1-PM) developed to identify risk groups, separating patients with favorable from others with dismal prognosis. A cohort of 539 clinically, biochemically, and genetically characterized Binet stage A patients were observed until progression, first-line treatment, or death. Multivariate analysis identified six independent factors associated with overall survival (OS) and time-to-first treatment (TTFT): del(17p), unmutated IGHV, del(11q), ß2-microglobulin >3.5 mg/dL, lymphocyte doubling time (LDT) <12 months, and age >60 years. These factors were integrated into the CLL1-PM, which stratified patients into four risk groups. The CLL1-PM was prognostic for OS and TTFT, e.g., the risk of treatment at 5 years was 85.9, 51.8, 27.6, and 11.3% for very low (0-1.5), low (2-4), high (4.5-6.5), and very high-risk (7-14) scores, respectively (P < 0.001). Notably, in addition to factors comprising CLL-IPI, we substantiated del(11q) and LDT as prognostic factors in early CLL. Altogether, our findings would be useful to effectively stratify Binet stage A patients, particularly within the scope of clinical trials evaluating novel agents.

In vivo detection of changes in cutaneous carotenoids after chemotherapy using shifted excitation resonance Raman difference and fluorescence spectroscopy.

BACKGROUND: Various cutaneous toxicities under chemotherapy indicate a local effect of chemotherapy by secretion after systemic application. Here, changes in the fluorescence and Raman spectral properties of the stratum corneum subsequent to intravenous chemotherapy were assessed. METHODS: Twenty healthy subjects and 20 cancer patients undergoing chemotherapy were included. Measurement time points in cancer patients were before the first cycle of chemotherapy (Tbase ) and immediately after intravenous application of the chemotherapy (T1 ). Healthy subjects were measured once without any further intervention. Measurements were conducted using an individually manufactured system consisting of a handheld probe and a wavelength-tunable diode laser-based 488 nm SHG light source. Hereby, changes in both skin fluorescence and shifted excitation resonance Raman difference spectroscopy (SERRDS) carotenoid signals were assessed. RESULTS: Healthy subjects showed significantly (P < .001) higher mean concentrations of carotenoids compared to cancer subjects at Tbase . An increase in fluorescence intensity was detected in almost all patients after chemotherapy, especially after doxorubicin infusion. Furthermore, a decrease in the carotenoid concentration in the skin after chemotherapy was found. CONCLUSION: The SERRDS based noninvasive detection can be used as an indirect quantitative assessment of fluorescent chemotherapeutics. The lower carotenoid SERRDS intensities at Tbase might be due to cancerous diseases and co-medication.

Influence of Sorafenib, Sunitinib and Capecitabine on the Antioxidant Status of the Skin.

BACKGROUND/AIM: The aim of the present study was to examine the effect of orally administered sorafenib (Nexavar®), sunitinib (Sutent®) and capecitabine (Xeloda®), which cause palmoplantar erythrodysesthesia (PPE), on the antioxidant status of the skin and the formation of free radicals. PATIENTS AND METHODS: A total of 42 patients were enrolled, of which 36 (85%) completed the study. Overall, 19 received capecitabine (2,000-4,000 mg per day), 10 sunitinib (25-50 mg per day) and 7 sorafenib (400-800 mg per day). Cutaneous carotenoids as markers of the antioxidant status of the skin were measured 1 day before the first oral administration (Tbase) and at day 18 of treatment (T1). RESULTS: The mean antioxidant concentrations increased significantly in patients treated with sunitinib from 3.99±1.01 to 4.68±1.32, p=0.047 and sorafenib from 4.83±0.74 to 5.3±0.78, p=0.007. Treatment with capecitabine did not significantly increase the mean antioxidant concentration. CONCLUSION: Formation of free radicals may not be the underlying patho-mechanism of tyrosine kinase inhibitors (TKI)- and capecitabine-associated PPE.

Influence of Chemotherapy on the Antioxidant Status of Human Skin.

BACKGROUND: Palmoplantar erythrodysesthesia is a frequent dermal side-effect during chemotherapy. Previous investigations showed radical formation subsequent to doxorubicin infusion and preventative and therapeutic effects of an antioxidant-containing ointment. PATIENTS AND METHODS: Using a non-invasive vivomeasuring system (Biozoom®; Biozoom Services GmbH, Kassel, Germany) changes in the antioxidant status (as measured by relative carotenoid concentration) of the skin prior to and after intravenous administration of paclitaxel, docetaxel and 5-fluorouracil were investigated in 42 patients with cancer. RESULTS: A significant decrease of antioxidant concentration subsequent to intravenous administration was found for all investigated chemotherapeutic agents. The mean concentration of carotenoids decreased from 3.59±1.26 arbitrary units (a.u.) to 3.41±1.28 a.u. (p<0.001) after paclitaxel administration, from 6.33±2.43 to 5.63±2.29 a.u. after docetaxel (p=0.027) and from 4.26±1.81 to 3.98±1.53 a.u. (p=0.042) after 5-fluorouracil infusion. CONCLUSION: Oxidative stress might play a significant role in the pathomechanism of palmoplantar erythrodysesthesia associated with paclitaxel, docetaxel and 5-fluorouracil. Therefore, an antioxidant-containing ointment might serve as preventative and therapeutic option.

Detection of capecitabine (Xeloda®) on the skin surface after oral administration.

Palmoplantar erythrodysesthesia (PPE), or hand-foot syndrome, is a cutaneous toxicity under various chemotherapeutics contributing to the most frequent side effects in patients treated with capecitabine (Xeloda®). The pathomechanism of PPE has been unclear. Here, the topical detection of capecitabine in the skin after oral application was shown in 10 patients receiving 2500 mg/m 2 /day 2500 mg/m2/day capecitabine. Sweat samples were taken prior to and one week after oral administration of capecitabine. Using high-resolution continuum source absorption spectrometry, the changes in concentrations of fluorine, which is an ingredient of capecitabine, were quantified and statistically analyzed. Here, we show an increase in fluorine concentrations from 40±10 ppb 40±10 ppb (2±0.5 pM 2±0.5 pM ) before capecitabine administration to 27.7±11.8 ppm 27.7±11.8 ppm (14.6±6.5 nM 14.6±6.5 nM ) after application, p<0.001 p<0.001 . The results show the secretion of capecitabine on the skin surface after oral administration, indicating a local toxic effect as a possible pathomechanism of PPE.

Bendamustine plus mitoxantrone for relapsed/refractory chronic lymphocytic leukaemia (CLL): results of a multicentre phase II study of the German CLL Study Group (GCLLSG).

The efficacy of bendamustine (50 mg/m², days 1-3) plus mitoxantrone (10 mg/m², day 1), every 28 days for up to four courses, was evaluated in a Phase II multicentre trial enrolling 59 patients with relapsed or refractory B-cell chronic lymphocytic leukaemia (CLL). Major toxicities were grade 3/4 leucopenia, thrombocytopenia and infections in 42%, 12% and 12% of patients, respectively. Complete and partial response was achieved in 5/59 and 25/29 patients, respectively (overall response rate, 51%). Median time to progression was 22 months (range 1-49 + ) and median survival 27 months (range 0-49 + ). The combination of bendamustine and mitoxantrone is an active regime in relapsed or refractory CLL.